Our primary defense against infectious disease and re-occurring illness are memory T and B cells. These critical arms of the immune system can also be potent aggressors against many forms of cancer. Developing effective vaccines to prevent infection and to treat chronic infection or cancer remains a formidable challenge primarily because we do not fully understand how memory T and B cells develop during immune responses. Recent work has significantly improved our knowledge of memory CDS T cell development during infection by outlining a complex differentiation process that occurs as CDS T cells transit through the different developmental stages (naive->effector->memory cell stages) of an immune response. More importantly, these studies gave rise to the identification of the cellular progenitors of memory CDS T cells. This investigator found a signature marker, the interleukin-7 receptor alpha-chain (IL-7Ralpha), that distinguished the subset of effector cells that would survive and develop into memory CDS T cells from those that would die. Thus, it is now possible to detect, isolate and manipulate the cells that will develop into protective memory CDS T cells, and this will greatly facilitate discovery of the mechanisms involved in memory T cell generation. This proposal aims to characterize the factors that regulate memory cell precursor development during viral and bacterial infection. Aim 1 will investigate how key features of infection, such as inflammatory cytokines and the duration of antigenic stimulation, and IL-7 controls formation of memory CDS T cell precursors. Aim 2 will examine 'where'memory CDS T cell progenitors form and test if secondary lymphoid organs are required. This Aim will also investigate how lymphoid organs are involved in generating different types of memory CDS T cells, such as central and effector memory T cells that provide different levels of protective immunity. Aim 3 will test if IL-7R signals can single-handedly drive the development of protective memory CDS T cells during acute infection and vaccination. IL-7R signaling is necessary for memory CDS T cell development, and this Aim will determine if it is sufficient or if additional signals are needed. At the conclusion of these studies, we will have a clearer understanding of the signals and mechanisms that control formation of memory CDS T cells during viral and bacterial infection, and this will greatly impact new generation vaccines and immunotherapies.